The pathophysiology of blue toe syndrome has several underlying causes that range from benign to life-threatening conditions. In this chapter, we organized them into three different categories: arterial inflow disease, venous outflow disease, and inherited blood conditions. Proper history and identification of distribution, temperature, skin integrity, and color changes aid in proper diagnosis and specific management. Acuity will help with the differential diagnosis, where conditions such as acrosyndromes will commonly have a sudden onset, while vasculitis will have a more surreptitious presentation. Although many conditions are self-limited, peripheral vascular disease tends to be progressive and warrants aggressive medical management.